Genetically-Encoded Technology in Synthetic Chemistry and Chemical Biology

Dr. Ratmir Derda - Assoc. Professor of Science - University of Alberta
RHPH 164
Date / Time: 
Thursday, April 11, 2019 - 4:00pm
Dr. Casey Krusemark
Genetically-encoded (GE) libraries of proteins are a major source of discovery of “biological”
drugs generating a $200 billion in sales in 2017. In Chemistry, GE libraries of 109 polypeptides
made of 20 natural amino acids represent an orthogonal “raw material for organic synthesis”.
Like canonical feedstock—petroleum-derived starting materials—GE-peptides are readily
available but have limited structural diversity and practical utility. Like petroleum, peptides can
be transformed to useful structures through multi-step organic synthesis. Departing from
traditional diversification of low-functionality, achiral starting materials, we employ “late stage”
modification of polar, functionality-rich, chiral molecules in water. Each transformation, when
optimized, can routinely convert billion starting materials to billion products at once.
I will focus on recent developments from our group that expands the use of GE-technologies
to Organic Chemistry and Chemical Biology. (1) Drug discovery for “undruggable targets”
necessitates new chemical scaffolds of large surface area that do not break down in aggressive
proteolytic environment encountered in serum or GI-tract. Using GE-libraries of peptides as a
starting material for multi-step organic synthesis, we produce GE-libraries of novel bicyclic
architectures that exhibit remarkable stability to proteolytic degradation. (2) We show that
libraries of phage-displayed peptides can tackle fundamental physical-organic questions such as
substrate control of Wittig reactions. (3) We develop approaches to generation of GE-libraries of
any chemicals not derived from peptides. As example, we constructed genetically encoded
“liquid glycan arrays (LiGA)”. LiGA is a reagent that can be combined with proteins, cells or
tissues, inorganic materials, such as ice and safely injected into animals. Simple DNA
sequencing then uncovers glycan-binding preferences of said proteins, cells, tissues, materials
(ice) or various immune cells and organs in live animals.

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